Rearranged during transfection (RET) is a member of the receptor tyrosine kinases belonging to the cadherin superfamily (Surgery, 2007, vol. 141, p. 96-99). RET tyrosine kinase has a transmembrane region in the middle and has a tyrosine kinase region at the carboxyl-terminal side and an extracellular region at the amino-terminal side. It is known that there are three types of proteins due to differences in carboxyl-terminal splicing (TRENDS in Genetics, 2006, vol. 22, p. 627-636: Reference a). RET forms a dimer via a ligand/GFR complex to thereby phosphorylate and activate its own tyrosine (Reference a).
There are reports showing that RET will be involved in oncogenesis upon alterations (point mutation, chromosomal translocation, chromosomal inversion, gene amplification) in RET gene. For example, in thyroid medullary cancer, it is reported that a point mutation in RET gene results in the expression of RET tyrosine kinase with oncogenic ability (Reference a). Moreover, in thyroid papillary cancer, it is reported that RET gene is fused with another gene (e.g., coiled-coil domain containing 6 (CCDC6) gene or nuclear receptor coactivator 4 (NCOA4) gene) by chromosomal inversion or chromosomal translocation to cause the expression of fused tyrosine kinase RET/PTC with oncogenic ability (European Journal of Endocrinology, 2006, vol. 155, p. 645-653). Further, in non-small cell lung cancer, it is reported that RET is fused with kinesin family protein 5B (KIF5B) gene, which is one of the molecules constituting motor protein complexes involved in intracellular microtubule transport, or with CCDC6 gene to cause non-small cell lung cancer by the constitutive tyrosine kinase activity of fused tyrosine kinase KIF5B-RET or CCDC6-RET with oncogenic ability (Nature Medicine. 2012, 18, p. 378-381, WO2012/014795). Moreover, it is reported that the fused tyrosine kinase NCOA4-RET or TRIM33-RET in which RET gene is fused with NCOA4 gene or TRIM33 (tripartite motif-containing 33) gene is present in non-small cell lung cancer patients (J Clin Oncol, 30 (35), Dec. 10, 2012, p. 4352-9; and Cancer Discov 2013 June, 3 (6). June 2013, p. 630-5).
In view of the foregoing, compounds having an inhibitory effect against RET tyrosinc kinase are very useful for cancer prevention and treatment.
As inhibitory substances of RET tyrosine kinase, multi-kinase inhibitors such as sorafenib, sunitinib, XL184, vandetanib and ponatinib are reported to have a cell growth inhibitory effect against cell lines expressing KIF5B-RET (Non-patent Document 1: J Clin Oncol 30, 2012, suppl; Abstract no: 7510). Moreover, it is reported that two patients who have RET fusion gene-positive non-small cell lung cancer exhibited partial response to the multi-kinase inhibitor cabozantinib (Non-Patent Document 2: Cancer Discov, 3 (6). June 2013, p. 630-5).
On the other hand, a tetracyclic compound having the following general formula is reported as an inhibitor of anaplastic lymphoma kinase (ALK), a receptor tyrosine kinase belonging to the insulin receptor family (Patent Document 1: WO2010/143664, Patent Document 2: WO2012/023597, Patent Document 3: Japanese Patent Laid-Open No. 2012-126711). This compound is useful as a therapeutic and/or prophylactic agent for tumors with a mutation in ALK gene.
(see the above patent gazette for details of substituents, etc.)
Moreover, it is reported that the following compound with a high concentration (1,000 nM) inhibits many kinases including RET in the Ambit Kinase Screening test (Non-Patent Document 3: Cancer Cell, 19 (5), p. 679-690, 2011, Supplemental Information):

However, there is no report showing that the tetracyclic compound found in Patent Document 1 and Non-patent Document 3 is useful as a therapeutic or prophylactic agent for cancers with a mutation in RET.
Moreover, it is reported that the ALK inhibitor crizotinib has no cell growth inhibitory activity against KIF51B-RET-expressing cells (Non-Patent Document 4: Nature Medicine. 2012, 18, p. 378-381).